DESCRIPTION (Applicant's Description): The overall goal of the K08 award is to permit Sarah Tannehill-Gregg, D.V.M. to devote full time for research training leading to a Ph.D. in experimental pathobiology, and for development into an independent scientist for a cancer in academia or biomedical research. Dr. Tannehill-Gregg has completed a residency in comparative pathology and one year of research training in the sponsor's laboratory. The research goals are to investigate the regulation of extracellular calcium and the role of transforming growth factor-beta in parathyroid hormone-related protein (PTHrP) expression and secretion by cancers of the lung. This will address an important medical question since PTHrP is expressed by many carcinomas and is responsible for inducing humoral hypercalcemia of malignancy. The action of TGFbeta may be a critical determinant in the overexpression of PTHrP by carcinomas and play an important role in the pathogenesis of cancer-associated hypercalcemia in human patients. The overall hypothesis to be tested is that TGFbeta production by lung carcinoma acts as an autocrine or paracrine against to stimulate PTHrP production by the carcinoma cells. Aim 1: Investigate expression of PTHrP, TGFbeta1-3 and TGFbeta receptors (I and II) and measure serum ionized calcium and PTHrP concentrations and urine excretion of calcium and phosphorus in humans with lung cancer. Aim 2: Investigate the regulation of PTHrP expression and secretion by TGFbeta in lung carcinomas in vitro using explant cultures from spontaneous human neoplasms and cultures of lung carcinoma cell lines. Aim 3: Investigate the molecular regulation of PTHrP mRNA steady state levels, stability, and alternate splicing by TGFbeta in vitro using lung carcinoma explants and cell lines. Dr. Tannehill-Gregg has developed preliminary data to support all three aims and a collaboration with Medical and Surgical Oncology to facilitate the in vivo studies. The cooperative efforts of Dr. Tannehill-Gregg, the sponsor, and co-investigators in the Department of Veterinary Biosciences, Comprehensive Cancer Center, James Cancer Research Hospital, Pulmonary Oncology and Thoracic Surgery Divisions, and Tissue Procurement Program at Ohio State University will provide a productive environment to complete this significant investigation. The studies will provide important new data on the function of PTHrP and TGFbeta in lung cancer in human patients. The combination of results from in vivo study, in vitro cultures, and mechanistic molecular experiments will contribute to the understanding of the role of PTHrP in lung cancer and provide insight into the pathogenesis of cancer-associated hypercalcemia.